Aberrant Autophagosome Formation Occurs Upon Small Molecule Inhibition of ULK1 Kinase Activity

Maria Zachari, Marianna Longo, Ian Ganley (Lead / Corresponding author)

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Abstract

Autophagy is a crucial homeostatic mechanism that mediates the degradation of damaged or excess intracellular components. Such components are engulfed and sequestered into double membrane autophagosomes, which deliver their contents to lysosomes for degradation. Autophagy plays a role in numerous human disorders and its pharmacological targeting by small molecules offers therapeutic potential. The serine/threonine kinase ULK1 (and its homologue ULK2) is the most upstream component of the autophagic machinery and is required for autophagy initiation. Here, we use the most selective and potent published ULK1 inhibitors to gain insights into ULK1 kinase function during autophagy. Treatment with all inhibitors blocked autophagy but also resulted in the limited formation of initial autophagosome-like structures, which appeared abnormal in size and did not traffic to lysosomes. We found that upon ULK1 inhibition, phosphatidylinositol 3-phosphate binding proteins are still recruited to forming autophagosomes, implying that ULK1 activity is not essential for Inhibitors
Original languageEnglish
Article numbere202000815
Pages (from-to)1-11
Number of pages11
JournalLife Science Alliance
Volume3
Issue number12
Early online date27 Oct 2020
DOIs
Publication statusE-pub ahead of print - 27 Oct 2020

Keywords

  • Autophagy
  • Autophagosome
  • Inhibitor
  • Kinase
  • ULK1

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